Cyclic Amine Derivatives Research Articles

Phenoxyalkyl cyclic and acyclic amine derivatives: what do they teach us about scaffold-based drug design?

Phenoxyalkyl cyclic and acyclic amine derivatives: what do they teach us about scaffold-based drug design?

Cyclic Amine Synthesis via Catalytic Radical-Polar Crossover Cycloadditions.

The rapid assembly of valuable cyclic amine architectures in a single step from simple precursors has been recognized as an ideal platform in term of efficiency and sustainability. Although a vast number of studies regarding cyclic amine synthesis has been reported, new synthetic disconnection approaches are still high in demand. Herein, we report a catalytic radical-polar crossover cycloaddition to cyclic amine synthesis triggered from primary sulfonamide under photoredox condition. This newly developed disconnection, comparable to established synthetic approaches, will allow to construct β, β-disubstituted cyclic amine and β-monosubstituted cyclic amine derivatives efficiently. This study highlights the unique utility of primary sulfonamide as a bifunctional reagent, which acts as a radical precursor and a nucleophile. The open-shell methodology demonstrates broad tolerance to various functional groups, drug derivatives and natural products in an economically and sustainable fashion.

Cyclic Amine Synthesis via Catalytic Radical‐Polar Crossover Cycloadditions

AbstractThe rapid assembly of valuable cyclic amine architectures in a single step from simple precursors has been recognized as an ideal platform in term of efficiency and sustainability. Although a vast number of studies regarding cyclic amine synthesis has been reported, new synthetic disconnection approaches are still high in demand. Herein, we report a catalytic radical‐polar crossover cycloaddition to cyclic amine synthesis triggered from primary sulfonamide under photoredox condition. This newly developed disconnection, comparable to established synthetic approaches, will allow to construct β, β‐disubstituted cyclic amine and β‐monosubstituted cyclic amine derivatives efficiently. This study highlights the unique utility of primary sulfonamide as a bifunctional reagent, which acts as a radical precursor and a nucleophile. The open‐shell methodology demonstrates broad tolerance to various functional groups, drug derivatives and natural products in an economically and sustainable fashion.

Design and Screening of New Lead Compounds for Autism Based on QSAR Model and Molecular Docking Studies.

The purpose of the present study aims to develop a satisfactory model for predicting pro-social and pro-cognitive effects on azinesulfonamides of cyclic amine derivatives as potential antipsychotics. The three dimensional-quantitative structure affinity relationship (3D-QSAR) study was performed on a series of azinesulfonamides of cyclic amine derivative using comparative molecular similarity indices analysis (CoMSIA). The best statistical model of CoMSIA q2, r2, SEE and F values are 0.664, 0.973, 0.087, and 82.344, respectively. Based on the model contour maps and the highest activity structure of the 43rd compound, serial new structures were designed and the 43k1 compound was selected as the best structure. The dock results showed a good binding of 43k1 with the protein (PDB ID: 6A93). The QSAR model analysis of the contour maps can help us to provide guidelines for finding novel potential antipsychotics.

Synthesis, computational molecular docking analysis and effectiveness on tyrosinase inhibition of kojic acid derivatives

Tyrosinase inhibitors have become increasingly important as whitening agents and for the treatment of pigmentary disorders. In this study, the synthesis of kojic acid derivatives having 2-substituted-3-hydroxy-6-hyroxymethyl/chloromethyl/methyl/morpholinomethylpiperidinyl- methyl/pyrrolidinylmethyl-4H-pyran-4-one structure (compounds 1–30) with inhibitory effects on tyrosinase enzyme were described. One-pot Mannich reaction was carried out by using kojic acid/chlorokojic acid/allomaltol and substituted benzylpiperazine derivatives in presence of formaline. Subsequently, cyclic amine (morpholine, piperidine and pyrrolidine) derivatives of the 6th-position of chlorokojic acid were obtained with nucleophilic substitutions in basic medium. The structures of new compounds were identified by FT-IR, 1H- and 13C NMR, ESI-MS and elemental analysis data. The potential mushroom tyrosinase inhibitory activity of the compounds were evaluated by the spectrophotometric method using l-DOPA as a substrate and kojic acid as the control agent. The potential inhibitory activity was also investigated in silico using molecular docking simulation method. Tyrosinase inhibitory action was significantly more efficacious for several compounds (IC50: 86.2–362.1 µM) than kojic acid (IC50: 418.2). Compound 3 bearing 3,4-dichlorobenzyl piperazine moiety was proven to have the highest inhibitory activity. The results of docking studies showed that according to the predicted conformation of compound 3 in the enzyme binding site, hydroxymethyl group provides a metal complex with copper ions and enzyme. Thus, this interaction explain the high inhibitory activities of the compounds 1, 3 and 4 possessing hydroxymethyl substituent supporting the mushroom assay results with docking studies. In accordance with the results, it is suggested that Mannich bases of kojic acid bearing substituted benzyl piperazine groups (compounds 1, 3, 4, 11, 13, 14, 23, 24, 28, and 29) could be promising antityrosinase agents. Additionally, considering the relationship between tyrosinase inhibitory activity results and molecular docking, a new tyrosinase inhibition mechanism can be proposed.

Synthesis and Cytotoxic Evaluation of Kojic Acid Derivatives with Inhibitory Activity on Melanogenesis in Human Melanoma Cells.

Malignant melanoma is an agressive tumour related to the overproduction of melanin, which provides colors of skin, eyes and hair. In addition contributing to the risk of malignant melanoma, abnormal production of melanin has many drawbacks, including hyperpigmentation, post-inflammatory pigmentation, melasma and skin aging. Kojic acid is currently employed in order to lighten skin pigmentation and provide depigmentation. Mannich bases of kojic acid with the structure of 2-substituted-3-hydroxy-6-hyroxymethyl/chloromethyl/ methyl/morpholinomethyl/piperidinylmethyl/pyrrolidinylmethyl-4H-pyran-4-one (compounds 1-23) were synthesized by the reaction of kojic acid/chlorokojic acid/allomaltol and substituted benzylpiperazine derivatives in the presence of formaline. To obtain the cyclic amine (morpholine, piperidine and pyrrolidine) derivatives, nucleophilic substitutions were carried out. Cytotoxic effects on A375 human malignant melanoma, HGF-1 human gingival fibroblasts, and MRC-5 human lung cell lines were investigated by sulphorhodamine B assay. Control agents were vemurafenib, dacarbazine, temozolomide, and lenalidomide, which are the commercially available drugs for the treatment of malignant melanoma. Cytotoxic action against melanoma cells was significantly more efficacious (IC50: 11.26-68.58 μM) than the FDA-approved drugs except for vemurafenib. Fourteen of the compounds were proven to have higher IC50 values for the non-cancerous cell lines, HGF-1, and MRC-5 cells. Melanogenesis inhibition assay was performed to observe the ability of the drugs to inhibit melanin production and certain compounds were shown to be capable of actively inhibiting melanin production in melanoma cells. Mannich bases of kojic acid derivatives may be promising therapeutic agents, since some have more potent effects on melanoma cells than previously FDA-approved drugs for the treatment of malignant melanoma.

Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects

Currently used antipsychotics are characterized by multireceptor mode of action. While antagonism of dopamine D2 receptors is responsible for the alleviation of “positive” symptoms of schizophrenia and the effects at other, particularly serotonergic receptors are necessary for their additional therapeutic effects, there is no consensus regarding an “ideal” target engagement. Here, a detailed SAR analysis in a series of 45 novel azinesulfonamides of cyclic amine derivatives, involving the aryl-piperazine/piperidine pharmacophore, central alicyclic amine and azinesulfonamide groups has led to the selection of (S)-4-((2-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)sulfonyl)isoquinoline (62). The polypharmacology profile of 62, characterized by partial 5-HT1AR agonism, 5-HT2A/5-HT7/D2/D3R antagonism, and blockade of SERT, reduced the “positive”-like, and “negative”-like symptoms of psychoses. Compound 62 produced no catalepsy, demonstrated a low hyperprolactinemia liability and displayed pro-cognitive effects in the novel object recognition task and attentional set-shifting test. While association of in vitro features with the promising in vivo profile of 62 is still not fully established, its clinical efficacy should be verified in further stages of development.

Synthesis of New Cyclic Amines-Linked Metronidazole Derivatives as Possible Prodrugs

Certain cyclic amine derivatives of metronidazole via acetate spacer were prepared. Cyclic amines used are piperidine and piperazine to improve the physicochemical properties and reduce some of metronidazole side effects. This is believed to be done by modification of its structural features to get prodrugs with improved properties over that of metronidazole. The present work includes esterification of metronidazole with choroacetic acid, N-alkylation of the cyclic amines by the halogenated ester and characterization of their structures by spectral(UV and IR) and elemental(CHN)analysis.The melting points, degree of solubilities and partition coefficients were also determined. Both metronidazole-piperazine and metronidazole-piperidine derivatives have different structural and physicochemical properties that may be excellent to diminish problems associated with metronidazole.
 Key words: Metronidazole, chloroacetate, prodrug.

Copper-Catalyzed Arylation with Diaryliodonium Salts

The unique reactivity of diaryliodonium salts with copper complexes has been applied to a variety of synthetic organic transformations. These hypervalent iodine compounds have been used for diverse copper-catalyzed cross-coupling reactions including C–H functionalizations, enantioselective C–C bond formation, cascade reactions and different heteroatom arylation processes. This review provides a summary of recent developments on this topic and discusses both the synthetic utility and mechanisms of these transformations. 1 Introduction 2 Historical Background 3 Arylation of Carbon Nucleophiles 3.1 Arylation of Organometallic Compounds 3.2 Arylation of Heteroarenes 3.3 Arylation of Arenes 3.4 Arylation of Alkenes 3.5 Arylation of Alkynes 4 Nitrogen Arylation 4.1 Arylation of Acyclic Amine Derivatives 4.2 Arylation of Cyclic Amine Derivatives 4.3 Arylation of Nitriles 4.4 Arylation of Azides 5 Oxygen Arylation 6 Arylation of Other Heteroatoms 6.1 Fluorine Arylation 6.2 Sulfur Arylation 6.3 Phosphorus Arylation 6.4 Iodine Arylation 7 Summary and Conclusions

ChemInform Abstract: Chiral Phosphoric Acid Catalyzed Oxidative Kinetic Resolution of Cyclic Secondary Amine Derivatives Including Tetrahydroquinolines by Hydrogen Transfer to Imines.

A chiral Bronsted acid catalyzed dehydrogenative kinetic resolution of tetrahydroquinoline derivatives, which are representative of cyclic secondary amines, based on their hydrogen transfer to aromatic imines was efficiently achieved with high enantioselectivities. This hydrogen transfer of tetrahydroquinolines to imines was not driven by their aromatization to quinolines. This dehydrogenative kinetic resolution could be also applied to the asymmetric synthesis of various benzofused heterocycles containing secondary amine cores.

N-Alkylation and N,C-Dialkylation of Amines with Alcohols in the Presence of Ruthenium Catalysts with Chelating N-Heterocyclic Carbene Ligands

A series of new benzimidazolium salts and ruthenium(II) complexes containing chelating N-heterocyclic carbenes (NHCs) functionalized with a benzylic group and an acetal group were prepared. All of the synthesized compounds were characterized by elemental analysis and NMR spectroscopy, and the molecular structures of 2c and 2d were determined by X-ray crystallography. All of the complexes were tested in the alkylation of cyclic amine derivatives with alcohols and showed excellent activity in this reaction. Cyclic amines were alkylated with primary and heteroaromatic alcohols. The Ru–NHC complexes also catalyzed N,C3-dialkylation of cyclic amines.

Chiral phosphoric acid catalyzed oxidative kinetic resolution of cyclic secondary amine derivatives including tetrahydroquinolines by hydrogen transfer to imines.

A chiral Brønsted acid catalyzed dehydrogenative kinetic resolution of tetrahydroquinoline derivatives, which are representative of cyclic secondary amines, based on their hydrogen transfer to aromatic imines was efficiently achieved with high enantioselectivities. This hydrogen transfer of tetrahydroquinolines to imines was not driven by their aromatization to quinolines. This dehydrogenative kinetic resolution could be also applied to the asymmetric synthesis of various benzofused heterocycles containing secondary amine cores.

Directed Ruthenium‐Catalyzed C(sp3)H α‐Alkylation of Cyclic Amines Using Dioxolane‐Protected Alkenones

AbstractA catalytic system for ruthenium‐catalyzed C(sp3)H α‐alkylation of piperidines with dioxolane‐protected alkenones is reported. Dioxolane protection of the ketone proved crucial to obtain alkylation products. A diverse set of highly substituted piperidines was readily prepared in moderate to good yields via this methodology from easily accessible starting materials (C‐2, C‐3 and C‐4 substituted piperidines). When the methodology is applied to C‐3 substituted piperidines, featuring two α positions, only monoalkylated products (2,5‐disubstituted) are observed. Even bicyclic amines, which feature a fused piperidine moiety, can be used. The successful directing group as well as protecting group (ketal) removal is also demonstrated. The methodology thus allows one to further derivatize and access hitherto unknown functionalized cyclic amine derivatives and will be useful in molecular library synthesis.magnified image

ChemInform Abstract: Anodic Selective Functionalization of Cyclic Amine Derivatives

AbstractReview: 105 refs.

Evaluation of WO2012037204 and WO2012037226: Exelixis' selective PI3Kδ inhibitors; the basis of a US$251 million deal

Two applications each claim compounds described as selective PI3Kδ inhibitors. The first claims 2-amino-3-substituted-8-methylquinoline derivatives. The second, more substantial, application claims a broad range of cyclic amine derivatives of 6-aminopurines. These are the first patent applications from Exelixis relating to its PI3Kδ inhibitor program despite its disclosure of the biological profile of its lead inhibitor XL-499 in late 2010.

Anodic Selective Functionalization of Cyclic Amine Derivatives

Anodic Selective Functionalization of Cyclic Amine Derivatives

Platinum-Catalyzed Diastereoselective Intramolecular Coupling of Allyl Halides and Hydrazones

Nucleophilic allyl platinum addition to hydrazones under platinum-catalyzed conditions was studied. To generate nucleophilic allyl platinum complexes, allyl halides were employed with platinum complexes, SnCl(2), and H(2). The allyl platinum(IV) intermediates reacted with the hydrazone to give the corresponding cyclic amine derivatives in good yield and with excellent diastereoselectivity. The cis selectivity of N-tethered substrates was attributed to a tight interaction of allyl platinum species with the hydrazone, on the basis of the results of solvent screening and acid/base addition experiments.

ChemInform Abstract: A Convenient Route to β-Aryl-Substituted Cyclic Enamines as Key Synthetic Intermediates of Sceletium and Amaryllidaceae Alkaloids.

Abstract Aryl groups were introduced into the position β to the nitrogen atom of cyclic amines by carrying out the anodic α-methoxylation of cyclic amine derivatives, the elimination of methanol from the oxidized products, the halomethoxylation of the resulting α,β-unsaturated cyclic amine derivatives, the replacement of the α-methoxy group with an aryl group, and the silver ion-promoted migration of the α-aryl group to the β-position, consecutively. This method was applied to the synthesis of some alkaloids such as (±)-mesembrine.

The stereodivergent aziridination of allylic carbamates, amides and sulfonamides

A stereodivergent protocol for the aziridination of a range of cyclic allylic amine derivatives has been developed. syn-Products can be obtained in >99:1 dr under H-bonded control and anti-products are obtained in >99:1 dr under steric control by judicious choice of the N-protecting groups.

ChemInform Abstract: Catalytic Activation of Trichlorosilane for Efficient and Stereoselective Reduction of Ketones.

Abstract Some kinds of N-formyl cyclic amine derivatives were found to be effective activators for trichlorosilane to reduce ketones. Namely, a catalytic amount of these activators were sufficient to complete the reduction of ketones with trichlorosilane, and the reduction of ketones by trichlorosilane with optically active activators gave enantiomerically enriched sec-alcohols in some extent of optical yields (up to 51% ee).